1. Field of the Invention
This invention relates to intermediates useful in preparing 4'-(2-carboxyethyl)phenyl trans-4-aminomethylcyclohexanecarboxylate (hereinafter referred to as CEP-ester), a compound which is pharmaceutically useful in an anti-plasmin agent or anti-peptic ulcer agent, and its therapeutically useful acid addition salts. More particularly it relates to novel esters which are easily hydrolyzed to yield CEP-ester, and to processes for producing CEP-ester using these novel esters.
2. Description of the Prior Art
Three processes are known for producing CEP-ester.
(I) The intermediate 4'-(2-benzyloxycarbonylethyl)phenyl trans-4-N-benzyloxycarbonyl aminomethylcyclohexanecarboxylate hydrochloride or 4'-(2-benzyloxycarbonylethyl)phenyl trans-4-aminomethylcyclohexanecarboxylate hydrochloride is catalytically reduced with hydrogen, whereby the benzyloxycarbonyl protecting groups are removed to yield CEP-ester. The necessary intermediates are obtained by condensing trans-4-N-benzyloxycarbonylaminomethylcyclohexanecarbonyl chloride or trans-4-aminomethylcyclohexanecarbonyl chloride, respectively, with benzyl 4-hydroxyphenylpropionate. This process is disclosed in Japanese Published Examined Patent Applications 19950/71 and 48978/77.
(II) The intermediate 4'-(2-tert-butoxycarbonylethyl)phenyl trans-4-aminomethylcyclohexanecarboxylate hydrochloride is treated with hydrogen halide-acetic acid to remove the carbonyl protecting group, i.e., the tert-butyl group, and thus yield CEP-ester. The intermediate is prepared by condensing trans-4-aminomethylcyclohexanecarbonyl chloride with tert-butyl 4-hydroxyphenylpropionate. This process is disclosed in Japanese Published Unexamined Patent Application No. 78143/73.
The use of special and very specific protecting groups in the two processes described above is essential for the following reasons. In the condensation reaction used to prepare the intermediates used in the processes the carboxyl group of the 4-hydroxyphenylpropionic acid must be protected to prevent it from reacting with the acid halide. Therefore, after the condensation reaction, the protective group which remains attached to the terminal carboxyl group must be selectively removed to obtain the target CEP-ester. The carboxyl group cannot be protected by forming a conventional ester because the phenyl ester linkage in CEP-ester is much more easily hydrolyzed than ester linkages generally and hence will be preferentially hydrolyzed with resulting cleavage of the molecule and poor yield of CEP-ester. Hence, the protective group must be a special group which is easily removed by catalytic hydrogenation or special conditions of hydrolysis.
This problem is well illustrated by the third conventional method of preparing CEP-ester which does not use a special protective group and accordingly, suffers from poor yield.
(iii) The intermediate 4'-(2-alkoxycarbonylethyl)phenyl trans-4-aminomethylcyclohexanecarboxylate or its acid addition salt is hydrolyzed in the presence of an acid catalyst to give CEP-ester. The intermediate is prepared by reacting an alkyl 4-hydroxyphenylpropionate with trans-4-aminomethylcyclohexanecarbonyl chloride. This process is disclosed in Japanese Published Unexamined Patent Application No. 17447/77.
Method (iii) is the simplest of the conventional processes for producing CEP-ester. However, since the yield is less than 35% it is not industrially advantageous. The low yield is due to the fact that the molecule contains two types of ester linkages, the phenyl ester linkage and the alkyl ester linkage. In hydrolysis the alkyl ester linkage is only slightly less stable than the phenyl ester linkage. Hence the alkyl ester linkage cannot be hydrolyzed exclusively and some of the phenyl ester linkages are hydrolyzed with resultant lowering of the yield.
Hence, a need has continued to exist for a method of preparing CEP-ester in good yield, without using special protecting groups for the terminal carboxyl group.